WO2004064846A1 - Compositions and methods for combination antiviral therapy - Google Patents

Compositions and methods for combination antiviral therapy Download PDF

Info

Publication number
WO2004064846A1
WO2004064846A1 PCT/US2004/000868 US2004000868W WO2004064846A1 WO 2004064846 A1 WO2004064846 A1 WO 2004064846A1 US 2004000868 W US2004000868 W US 2004000868W WO 2004064846 A1 WO2004064846 A1 WO 2004064846A1
Authority
WO
WIPO (PCT)
Prior art keywords
emtricitabine
physiologically functional
functional derivative
combination
amino
Prior art date
Application number
PCT/US2004/000868
Other languages
English (en)
French (fr)
Inventor
Terrence C. Dahl
Mark M. Menning
Reza Oliyai
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32776014&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2004064846(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to CA 2512319 priority Critical patent/CA2512319A1/en
Priority to JP2006500943A priority patent/JP2006515624A/ja
Priority to US10/540,782 priority patent/US20060234982A1/en
Priority to EP20040701840 priority patent/EP1585527A1/en
Priority to AU2004206827A priority patent/AU2004206827A1/en
Publication of WO2004064846A1 publication Critical patent/WO2004064846A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • FTC is 4-amino-5-fluoro-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)- pyrimidin-2-one and includes all diastereomers, enantiomers, and mixtures thereof, in any proportion.
  • FTC includes the single enantiomer emtricitabine.
  • Therapeutic combinations and pharmaceutical compositions and formulations of the invention include the combination of phosphonamidate PMEA or PMPA compounds with FTC or (2R,5S,cis)-4-arnino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)- (lH)-pyrimidin-2-one (3TC, Lamivudine, EpivirTM), and their use in the treatment of HTV infections.
  • Another aspect of the invention is a patient pack comprising at least one, typically two, and optionally, three active ingredients selected from GS-7340, emtricitabine, and other antiviral agents, and an information insert containing directions on the use of GS-7340 and emtricitabine together in combination.
  • chemical stability means that the two primary antiviral agents in combination are substantially stable to chemical degradation. Preferably, they are sufficiently stable in physical combination to permit commercially useful shelf life of the combination product.
  • chemically stable means that a first component of the mixture does not act to degrade a second component when the two are brought into physical combination to form a pharmaceutical dosage form. More typically, “chemically stable” means that the acidity of a first component does not catalyzes or otherwise accelerate the acid decomposition of a second component.
  • “chemically stable” means that GS-7340 is not substantially degraded by the acidity of emtricitabine.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a synergistic anti- viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
  • physiologically functional derivative means a pharmaceutically active compound with equivalent or near equivalent physiological functionality to GS- 7340 or emtricitabine when administered in combination with another pharmaceutically active compound in a combination of the invention.
  • Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113- 191). Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A "prodrug” is thus a covalently modified analog of a therapeutically-active compound.
  • Alkyl means a saturated or unsaturated, branched, straight-chain, branched, or cyclic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne.
  • Typical alkyl groups consist of 1-18 saturated and/or unsaturated carbons, such as normal, secondary, tertiary or cyclic carbon atoms.
  • CAS Registry Numbers for GS-7340 include: 379270-37-8 and for GS-7340 fumarate include: 379270-38-9.
  • PMPA US Patent Nos. 4808716, 5733788, 6057305
  • R 6 and R 8 are independently selected from H, C ⁇ -C 6 alkyl, C ⁇ -C 6 substituted alkyl, C 6 -C 2 o aryl, C 6 -C 2u substituted aryl, C 6 -C 2 o arylalkyl, C 6 -C 2 o substituted arylalkyl.
  • R 7 is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and which, if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group.
  • R 7 may be H, CH 3 or CH(CH 3 ) 2 .
  • the phosphonamidate PMEA and PMPA compound may be enantiomerically- enriched or purified (single stereoisomer) where the carbon atom bearing R 5 may be the R or S enantiomer when R 5 is not H.
  • the phosphonamidate PMEA and PMPA compound may be a racemate, i.e. a mixture of R and S stereoisomers.
  • the invention includes all enantiomers, diastereomers, racemates, and enriched stereoisomer mixtures of phosphonamidate PMEA and PMPA compounds.
  • the single enantiomer emtricitabine has the structure:
  • GS-7340 and emtricitabine may exist in keto or enol tautomeric forms and the use of any tautomeric form is within the scope of this invention.
  • GS-7340 and emtricitabine will normally be utilized in the combinations of the invention substantially free of the corresponding enantiomer, that is to say no more than about 5% w/w of the corresponding enantiomer will be present.
  • R is H, -Cis alkyl, Ci-Cis substituted alkyl, C 2 -C ⁇ 8 alkenyl, C 2 -C ⁇ 8 substituted alkenyl, C 2 -C ⁇ 8 alkynyl, C 2 -Ci 8 substituted alkynyl, C 6 -C u aryl, C 6 -C 2 o substituted aryl, C 2 -C 2 o heterocycle, C -C 2 o substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy, or a prodrug moiety
  • Physiologically functional derivatives of emtricitabine also include 3TC
  • Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate.
  • enzymes e.g. esterases, oxidases, etc.
  • Prodrug esters in accordance with the invention are independently selected from the following groups: (1) mono-, di-, and tri-phosphate esters of GS-7340 or emtricitabine or any other compound which upon administration to a human subject is capable of providing (directly or indirectly) said mono-, di, or triphosphate ester; (2) carboxylic acid esters (3) sulfonate esters, such as alkyl- or aralkylsulfonyl- (for example, methanesulfonyl); (4) amino acid esters (for example, alanine, L-valyl or L- isoleucyl); (5) phosphonate; and (6) phosphonamidate esters.
  • prodrugs refer to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base solvolysis, to form an active ingredient.
  • Typical examples of prodrugs of the active ingredients of the combinations of the invention have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions or liposome formulations.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Tenofovir disoproxil include: [2-(6-amino-purin- 9-yl)-l-methyl-ethoxymethyl] -phosphonic acid diisopropoxycarbonyloxymethyl ester; and 2,4,6, 8-tetraoxa-5-phosphanonanedioic acid, 5-[[(lR)-2-(6-amino-9H-purin-9-yl)- l-methylethoxy]methyl]-, bis(l-methylethyl) ester, 5-oxide.
  • the CAS Registry numbers include: 201341-05-1; 202138-50-9; 206184-49-8.
  • a further aspect of the invention is a patient pack comprising at least one active ingredient GS-7340, emtricitabine or a physiologically functional derivative of either of the combination and an information package or product insert containing directions on the use of the combination of the invention.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Exemplary unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • the compounds of the combination of the present invention may be obtained in a conventional manner, known to those skilled in the art.
  • Tenofovir disoproxil fumarate can be prepared, for example, as described in US Patent No. 5977089. Methods for the preparation of FTC are described in WO 92/14743, incorporated herein by reference.
  • PBMC peripheral blood mononuclear cells
  • Combination assays may be performed at varying concentrations of the compounds of the combinations to determine EC 50 by serial dilutions.
  • compositions A, B, C, D, E, and F are prepared by wet granulation of the ingredients with an aqueous solution, addition of extragranular components and then followed by addition of magnesium stearate and compression. mg/ tablet
  • Purified water is added and mixed well before use.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • AIDS & HIV (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/US2004/000868 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy WO2004064846A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA 2512319 CA2512319A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy
JP2006500943A JP2006515624A (ja) 2003-01-14 2004-01-13 組み合わせ抗ウイルス療法のための組成物および方法
US10/540,782 US20060234982A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy
EP20040701840 EP1585527A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy
AU2004206827A AU2004206827A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US44030803P 2003-01-14 2003-01-14
US44024603P 2003-01-14 2003-01-14
US60/440,308 2003-01-14
US60/440,246 2003-01-14

Publications (1)

Publication Number Publication Date
WO2004064846A1 true WO2004064846A1 (en) 2004-08-05

Family

ID=32776014

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2004/000868 WO2004064846A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy
PCT/US2004/000832 WO2004064845A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2004/000832 WO2004064845A1 (en) 2003-01-14 2004-01-13 Compositions and methods for combination antiviral therapy

Country Status (26)

Country Link
US (11) US20040224916A1 (ja)
EP (4) EP3025718A1 (ja)
JP (8) JP4996241B2 (ja)
KR (3) KR100860136B1 (ja)
CN (2) CN102670629B (ja)
AP (1) AP2089A (ja)
AT (1) ATE398455T1 (ja)
AU (3) AU2004206821C1 (ja)
BR (1) BRPI0406760A (ja)
CA (2) CA2512319A1 (ja)
CY (1) CY1108355T1 (ja)
DE (1) DE602004014470D1 (ja)
DK (1) DK1583542T3 (ja)
EA (2) EA015145B1 (ja)
ES (1) ES2308136T3 (ja)
HK (1) HK1079122A1 (ja)
HR (2) HRP20050619A2 (ja)
IL (1) IL169243A (ja)
IS (1) IS7977A (ja)
MX (1) MXPA05007016A (ja)
NO (3) NO337917B1 (ja)
NZ (1) NZ540728A (ja)
PL (2) PL408254A1 (ja)
PT (1) PT1583542E (ja)
SI (1) SI1583542T1 (ja)
WO (2) WO2004064846A1 (ja)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013115916A1 (en) * 2012-02-03 2013-08-08 Gilead Sciences, Inc. Combination therapy comprising gs-7340 and cobicistat for use in the treatment of viral infections
WO2015028875A3 (en) * 2013-08-29 2015-11-19 Teva Pharmaceuticals Industries Ltd. Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir
EP1819323B1 (en) 2004-12-03 2016-11-16 Merck Sharp & Dohme Corp. Pharmaceutical composition containing an anti-nucleating agent
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
WO2018153977A1 (en) * 2017-02-24 2018-08-30 Hexal Ag Stable composition of tenofovir alafenamide
WO2019113462A1 (en) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Families Citing this family (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI1583542T1 (sl) 2003-01-14 2008-12-31 Gilead Sciences Inc Sestavki in postopki za kombinacijsko antivirusnoterapijo
US20070003608A1 (en) * 2005-04-08 2007-01-04 Almond Merrick R Compounds, compositions and methods for the treatment of viral infections and other medical disorders
WO2006110655A2 (en) * 2005-04-08 2006-10-19 Chimerix, Inc. Compounds, compositions and methods for the treatment of poxvirus infections
TWI375560B (en) * 2005-06-13 2012-11-01 Gilead Sciences Inc Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same
TWI471145B (zh) * 2005-06-13 2015-02-01 Bristol Myers Squibb & Gilead Sciences Llc 單一式藥學劑量型
US8297028B2 (en) 2006-06-14 2012-10-30 The Invention Science Fund I, Llc Individualized pharmaceutical selection and packaging
US8000981B2 (en) 2005-11-30 2011-08-16 The Invention Science Fund I, Llc Methods and systems related to receiving nutraceutical associated information
US7927787B2 (en) 2006-06-28 2011-04-19 The Invention Science Fund I, Llc Methods and systems for analysis of nutraceutical associated components
US8340944B2 (en) 2005-11-30 2012-12-25 The Invention Science Fund I, Llc Computational and/or control systems and methods related to nutraceutical agent selection and dosing
US20080103746A1 (en) 2005-11-30 2008-05-01 Searete Llc, A Limited Liability Corporation Systems and methods for pathogen detection and response
US7974856B2 (en) 2005-11-30 2011-07-05 The Invention Science Fund I, Llc Computational systems and methods related to nutraceuticals
US7827042B2 (en) 2005-11-30 2010-11-02 The Invention Science Fund I, Inc Methods and systems related to transmission of nutraceutical associated information
US10296720B2 (en) 2005-11-30 2019-05-21 Gearbox Llc Computational systems and methods related to nutraceuticals
ATE474560T1 (de) * 2005-12-14 2010-08-15 Cipla Ltd Pharmazeutische kombination aus nucleotid und nucleosid-reverse-transkriptase-hemmern (wie tenofovir und lamivudin) in verschiedenen teilen der dosiereinheit
US9044509B2 (en) 2006-02-03 2015-06-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibition of HIV infection through chemoprophylaxis
AU2007275860C1 (en) 2006-07-07 2014-06-12 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
EP2109570A1 (de) * 2007-01-20 2009-10-21 Merck Patent GmbH Packung enthaltend weichkapseln
WO2008096369A2 (en) * 2007-02-05 2008-08-14 Matrix Laboratories Limited Pharmaceutical formulation for use in hiv therapy
US20100196273A1 (en) * 2007-02-12 2010-08-05 Board Of Regents, University Of Texas System Novel agent for in vivo pet imaging of tumor proliferation
LT2487166T (lt) 2007-02-23 2016-11-10 Gilead Sciences, Inc. Terapinių agentų farmakokinetinių savybių moduliatoriai
CN101820863A (zh) * 2007-10-10 2010-09-01 马林克罗特贝克公司 直接可压制的高功能性颗粒状微晶纤维素基赋形剂、其制备方法和用途
US20100055180A1 (en) * 2007-10-10 2010-03-04 Mallinckrodt Baker, Inc. Directly Compressible Granular Microcrystalline Cellulose Based Excipient, Manufacturing Process and Use Thereof
US8609609B2 (en) 2008-01-18 2013-12-17 North Carolina State University Peptides and methods of use as therapeutics and screening agents
CA2713105C (en) 2008-01-25 2016-06-07 Chimerix, Inc. Methods of treating viral infections
US7935817B2 (en) * 2008-03-31 2011-05-03 Apotex Pharmachem Inc. Salt form and cocrystals of adefovir dipivoxil and processes for preparation thereof
MX2010011963A (es) 2008-05-02 2010-12-06 Gilead Sciences Inc Uso de particulas trasportadoras solidas para mejorar la capacidad de procesamiento de un agente farmaceutico.
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
PA8855801A1 (es) 2008-12-23 2010-07-27 Sintesis de nucleosidos de purina
NZ593648A (en) 2008-12-23 2013-09-27 Gilead Pharmasset Llc Nucleoside phosphoramidates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
NZ594214A (en) 2009-02-06 2013-05-31 Gilead Sciences Inc Tablets comprising cobicistat, elvitegravir, emtricitabine and tenofovir disoproxil fumarate for combination therapy
TWI576352B (zh) 2009-05-20 2017-04-01 基利法瑪席特有限責任公司 核苷磷醯胺
US8614200B2 (en) 2009-07-21 2013-12-24 Chimerix, Inc. Compounds, compositions and methods for treating ocular conditions
MX356891B (es) 2010-01-27 2018-06-19 Viiv Healthcare Co Combinaciones de compuestos que comprenden inhibidores de la integrasa de vih y otros agentes terapéuticos.
PL2534150T3 (pl) 2010-02-12 2017-09-29 Chimerix, Inc. Sposoby leczenia infekcji wirusowej
SI2609923T1 (sl) 2010-03-31 2017-10-30 Gilead Pharmasset Llc Postopek za kristalizacijo (s)-izopropil 2-(((s)-(perfluorofenoksi) (fenoksi)fosforil)amino)propanoata
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
ES2551944T3 (es) 2010-03-31 2015-11-24 Gilead Pharmasset Llc (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihidropirimidin-1-(2H)-il)-4-fluoro-3-hidroxi-4-metiltetrahidrofuran-2-il)metoxi)(fenoxi)fosforil)amino)propanoato de isopropilo cristalino
CA2797601A1 (en) 2010-04-26 2011-11-10 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
EP2389929A1 (en) * 2010-05-30 2011-11-30 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Pharmaceutical formulations of tenofovir
EP2579892A2 (en) 2010-06-09 2013-04-17 Vaccine Technologies, Incorporated Therapeutic immunization in hiv infected subjects receiving stable antiretroviral treatment
JP2013535475A (ja) * 2010-08-01 2013-09-12 江蘇正大天晴薬業股▲ふん▼有限公司 フマル酸テノホビルジソプロキシルの結晶
UA114075C2 (xx) * 2010-11-19 2017-04-25 БАГАТОШАРОВА ТАБЛЕТКА, ЩО МІСТИТЬ РИЛПІВІРИН HCl, ЕМТРИЦИТАБІН І ТЕНОФОВІРУ ДИЗОПРОКСИЛФУМАРАТ
JP6069215B2 (ja) 2010-11-30 2017-02-01 ギリアド ファーマセット エルエルシー 化合物
WO2012154698A2 (en) * 2011-05-06 2012-11-15 Mckenna Charles E Method to improve antiviral activity of nucleotide analogue drugs
EP2785184B1 (en) 2011-11-30 2020-06-10 Emory University Compositions comprising jak inhibitors and haart drugs for use in the prevention or treatment of hiv
EA026138B1 (ru) 2012-02-03 2017-03-31 Джилид Сайэнс, Инк. Комбинированная терапия, включающая тенофовир алафенамида гемифумарат и кобицистат, для применения для лечения вирусных инфекций
CN107312039B (zh) 2012-08-30 2019-06-25 江苏豪森药业集团有限公司 一种替诺福韦前药的制备方法
KR102186030B1 (ko) * 2012-10-29 2020-12-03 시플라 리미티드 항 바이러스성 포스포네이트 유사체 및 이의 제조를 위한 방법
CN111303152B (zh) 2012-12-21 2023-04-11 吉利德科学公司 多环-氨基甲酰基吡啶酮化合物及其药物用途
CN103127028A (zh) * 2013-03-14 2013-06-05 南京恒道医药科技有限公司 一种含有富马酸替诺福韦二吡呋酯的胶囊剂
DK3019503T3 (da) 2013-07-12 2017-11-20 Gilead Sciences Inc Polycykliske-carbamoylpyridon-forbindelser og anvendelse deraf til behandling af hiv-infektioner
NO2865735T3 (ja) 2013-07-12 2018-07-21
CZ2013985A3 (cs) * 2013-12-09 2015-06-17 Zentiva, K.S. Stabilní farmaceutická kompozice obsahující tenofovir disoproxil fumarát
TWI660965B (zh) 2014-01-15 2019-06-01 美商基利科學股份有限公司 泰諾福韋之固體形式
WO2015155673A1 (en) 2014-04-08 2015-10-15 Teva Pharmaceutical Industries Ltd Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir
NO2717902T3 (ja) 2014-06-20 2018-06-23
TWI744723B (zh) 2014-06-20 2021-11-01 美商基利科學股份有限公司 多環型胺甲醯基吡啶酮化合物之合成
TW201613936A (en) 2014-06-20 2016-04-16 Gilead Sciences Inc Crystalline forms of(2R,5S,13aR)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
CN105399771B (zh) * 2014-07-21 2020-11-24 江苏豪森药业集团有限公司 替诺福韦前药晶型及其制备方法和用途
TWI695003B (zh) 2014-12-23 2020-06-01 美商基利科學股份有限公司 多環胺甲醯基吡啶酮化合物及其醫藥用途
CN107223052A (zh) * 2015-03-27 2017-09-29 豪夫迈·罗氏有限公司 包含sembragiline的药物制剂
EP3466490B1 (en) 2015-04-02 2020-10-21 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
AU2016287500B2 (en) * 2015-06-30 2019-05-02 Gilead Sciences, Inc. Pharmaceutical formulations comprising tenofovir and emtricitabine
TWI620754B (zh) * 2015-08-26 2018-04-11 Method for preparing amino phosphate derivative and preparation method thereof
EP3346995B1 (en) * 2015-11-09 2019-08-28 Gilead Sciences, Inc. Therapeutic compositions for treatment of human immunodeficiency virus
WO2017106069A1 (en) 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Antiviral oxime phosphoramide compounds
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
CN109562113A (zh) 2016-05-10 2019-04-02 C4医药公司 用于靶蛋白降解的螺环降解决定子体
EP3454856A4 (en) 2016-05-10 2019-12-25 C4 Therapeutics, Inc. HETEROCYCLIC DEGRONIMERS FOR TARGET PROTEIN REDUCTION
WO2018039157A1 (en) * 2016-08-25 2018-03-01 Merck Sharp & Dohme Corp. Antiviral prodrugs of tenofovir
WO2018080903A1 (en) 2016-10-26 2018-05-03 Merck Sharp & Dohme Corp. Antiviral aryl-amide phosphodiamide compounds
TR201617448A2 (tr) * 2016-11-29 2018-06-21 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Tenofovi̇r ve emtri̇si̇tabi̇n i̇çeren kati oral farmasöti̇k bi̇leşi̇mler
KR20190100249A (ko) 2016-12-22 2019-08-28 머크 샤프 앤드 돔 코포레이션 항바이러스 벤질-아민 포스포디아미드 화합물
CN106749254B (zh) * 2017-01-10 2018-05-25 青岛科技大学 一种6-氨基嘌呤乙基萘乙酸酯类化合物及其作为植物生长调节剂的用途
GB201705087D0 (en) * 2017-03-30 2017-05-17 Univ Liverpool Method for producing a liquid composition
EP3612226A1 (en) * 2017-04-18 2020-02-26 Cipla Limited Combination therapy for use in treating retroviral infections
RU2662160C9 (ru) 2017-07-03 2018-10-22 Александрович Иващенко Андрей Комбинированный лекарственный препарат для терапии вирусных инфекций
KR102077060B1 (ko) * 2017-07-14 2020-02-13 주식회사 종근당 테노포비어 디소프록실 아스파르트산 염을 포함하는 약제학적 조성물
RU2666727C1 (ru) * 2017-07-18 2018-09-12 Андрей Александрович Иващенко Ингибитор вируса гепатита В (ВГВ)
TR201713954A2 (tr) 2017-09-20 2019-04-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Tenofovir, emtrisitabin ve efavirenzin farmasötik kombinasyonlari
US11826375B2 (en) 2018-07-19 2023-11-28 Merck Sharp & Dohme Llc Phosphinic amide prodrugs of tenofovir
RU2726210C2 (ru) * 2018-12-27 2020-07-09 Общество С Ограниченной Ответственностью "Пролонгированные Лекарства" Комбинация противовирусных средств, набор и способ лечения на ее основе
CN110261631A (zh) * 2019-07-26 2019-09-20 重庆德方信息技术有限公司 用于健康检测装置的滴液机构
CN110251476B (zh) * 2019-08-01 2022-08-09 海思科制药(眉山)有限公司 一种恩曲他滨替诺福韦药物组合物
WO2022089600A1 (zh) * 2020-10-30 2022-05-05 杭州拉林智能科技有限公司 黄酮苷-有机胺类抗微生物剂复盐化合物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025797A1 (en) * 1998-11-02 2000-05-11 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis b virus
WO2002008241A2 (en) * 2000-07-21 2002-01-31 Gilead Sciences, Inc. Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same

Family Cites Families (131)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US568164A (en) 1896-09-22 Motor attachment for bicycles
CH389608A (de) 1960-01-19 1965-03-31 Sandoz Ag Verfahren zur Herstellung von neuen Äthern
US3524846A (en) * 1967-06-02 1970-08-18 Syntex Corp Process for the didealkylation of phosphonate esters
US3622677A (en) 1969-07-07 1971-11-23 Staley Mfg Co A E Compressed tablets containing compacted starch as binder-disintegrant ingredient
CH531000A (de) * 1970-03-11 1972-11-30 Sandoz Ag Verfahren zur Herstellung neuer Benzocycloheptathiophene
US3994974A (en) * 1972-02-05 1976-11-30 Yamanouchi Pharmaceutical Co., Ltd. α-Aminomethylbenzyl alcohol derivatives
US4003878A (en) * 1972-12-07 1977-01-18 Avtex Fibers Inc. Method of preparing an alkali-metal salt of an alkoxysulfonated benzoic acid glycol ester
GB1523865A (en) 1974-09-02 1978-09-06 Wellcome Found Purine compunds and salts thereof
DE2645710C2 (de) * 1976-10-09 1985-06-27 Merck Patent Gmbh, 6100 Darmstadt Phenoxy-amino-propanole, Verfahren zu ihrer Herstellung und pharmazeutische Zubereitung
US4384005A (en) 1980-09-26 1983-05-17 General Foods Corporation Non-friable, readily-soluble, compressed tablets and process for preparing same
GB2111043B (en) 1980-12-12 1985-02-06 Ciba Geigy Ag Novel cephalosporin esters
US4355032B2 (en) * 1981-05-21 1990-10-30 9-(1,3-dihydroxy-2-propoxymethyl)guanine as antiviral agent
JPS5879983A (ja) * 1981-11-06 1983-05-13 Kanebo Ltd 新規なベンズイミダゾ−ル誘導体、その製造法およびその医薬組成物
US4816570A (en) 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4476248A (en) * 1983-02-28 1984-10-09 The Upjohn Company Crystallization of ibuprofen
EP0141927B1 (en) * 1983-08-18 1991-10-30 Beecham Group Plc Antiviral guanine derivatives
US5155268A (en) * 1984-05-04 1992-10-13 The Upjohn Company Antiarrhythmic N-aminoalkylene alkyl and aryl sulfonamides
DE3582399D1 (de) 1984-09-20 1991-05-08 Beecham Group Plc Purin-derivate und ihre pharmazeutische verwendung.
CS263952B1 (en) 1985-04-25 1989-05-12 Holy Antonin Remedy with antiviral effect
CS263951B1 (en) 1985-04-25 1989-05-12 Antonin Holy 9-(phosponylmethoxyalkyl)adenines and method of their preparation
GB8607684D0 (en) * 1986-03-27 1986-04-30 Ici America Inc Thiazepine compounds
US4968788A (en) 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
CS264222B1 (en) * 1986-07-18 1989-06-13 Holy Antonin N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them
AU613592B2 (en) 1986-11-18 1991-08-08 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiviral phosophonomethoxy-alkyene purine and pyrimide derivatives
WO1988005438A1 (en) 1987-01-20 1988-07-28 Sri International Antiviral agents
GB8719367D0 (en) * 1987-08-15 1987-09-23 Wellcome Found Therapeutic compounds
ZA885709B (en) 1987-08-19 1989-04-26 Fujisawa Pharmaceutical Co Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer)
US5684164A (en) 1988-04-11 1997-11-04 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US5047407A (en) 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
US5466806A (en) 1989-02-08 1995-11-14 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US5453503A (en) 1988-10-11 1995-09-26 Eli Lilly And Company Azetidinone intermediates to carbacephalosporins and process
CA2001715C (en) 1988-11-14 1999-12-28 Muzammil M. Mansuri Carbocyclic nucleosides and nucleotides
UA45942A (uk) * 1989-02-08 2002-05-15 Біокем Фарма, Інк. 1,3-оксатіолан, його похідні, спосіб (варіанти) його одержання та фармацевтична композиція
US6642245B1 (en) 1990-02-01 2003-11-04 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US5204466A (en) 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US6069252A (en) 1990-02-01 2000-05-30 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US6703396B1 (en) 1990-02-01 2004-03-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers
GB9009861D0 (en) 1990-05-02 1990-06-27 Glaxo Group Ltd Chemical compounds
WO1991019721A1 (en) 1990-06-13 1991-12-26 Arnold Glazier Phosphorous produgs
US5177064A (en) * 1990-07-13 1993-01-05 University Of Florida Targeted drug delivery via phosphonate derivatives
CA2087446A1 (en) 1990-07-19 1992-01-20 Michael R. Harnden Antiviral phosphono-alken derivatives of purines
ATE194142T1 (de) * 1990-08-10 2000-07-15 Acad Of Science Czech Republic Verfahren zur herstellung von nukleotiden
DE69129650T2 (de) 1990-09-14 1999-03-25 Acad Of Science Czech Republic Wirkstoffvorläufer von Phosphonaten
CA2054126A1 (en) 1990-10-26 1992-04-27 Michiyuki Sendai Cephem compounds, their production and use
US5587480A (en) * 1990-11-13 1996-12-24 Biochem Pharma, Inc. Substituted 1,3-oxathiolanes and substituted 1,3-dithiolanes with antiviral properties
US5208221A (en) * 1990-11-29 1993-05-04 Bristol-Myers Squibb Company Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives
GB9026164D0 (en) 1990-12-01 1991-01-16 Beecham Group Plc Pharmaceuticals
US5179104A (en) * 1990-12-05 1993-01-12 University Of Georgia Research Foundation, Inc. Process for the preparation of enantiomerically pure β-D-(-)-dioxolane-nucleosides
US5672697A (en) 1991-02-08 1997-09-30 Gilead Sciences, Inc. Nucleoside 5'-methylene phosphonates
NZ250842A (en) 1991-02-22 1996-03-26 Univ Emory Resolution of a racemic mixture of nucleoside enantiomers such as 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (ftc)
US6812233B1 (en) 1991-03-06 2004-11-02 Emory University Therapeutic nucleosides
DE69206876T3 (de) * 1991-05-16 2004-08-12 Glaxo Group Ltd., Greenford Nukleosidanalogen enthaltende Antiviren-Zubereitungen
GB9110874D0 (en) 1991-05-20 1991-07-10 Iaf Biochem Int Medicaments
ZA923640B (en) * 1991-05-21 1993-02-24 Iaf Biochem Int Processes for the diastereoselective synthesis of nucleosides
GB9111902D0 (en) 1991-06-03 1991-07-24 Glaxo Group Ltd Chemical compounds
GB9116601D0 (en) 1991-08-01 1991-09-18 Iaf Biochem Int 1,3-oxathiolane nucleoside analogues
US6177435B1 (en) * 1992-05-13 2001-01-23 Glaxo Wellcome Inc. Therapeutic combinations
US5480875A (en) 1992-06-23 1996-01-02 Yamanouchi Pharmaceutical Co., Ltd. Crystal of monohydrate of heterocyclic bis(phosphonic acid) derivative
US5532225A (en) 1992-07-31 1996-07-02 Sri International Acyclic purine phosphonate nucleotide analogs as antiviral agents, and related synthetic methods
US5432172A (en) 1992-08-03 1995-07-11 The Research Foundation Of State University Of New York Biological applications of alkaloids derived from the tunicate Eudistoma sp.
US6057305A (en) 1992-08-05 2000-05-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
US5519021A (en) 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
NZ248852A (en) 1992-10-28 1997-06-24 Squibb & Sons Inc Alpha-phosphono and phosphinosulphonates and medicaments thereof
WO1994018215A1 (en) * 1993-02-03 1994-08-18 Gensia, Inc. Adenosine kinase inhibitors comprising lyxofuranosyl derivatives
US5514798A (en) * 1993-06-02 1996-05-07 Gilead Sciences, Inc. Method and cyclic carbonates for nucleotide analogues
GB9311709D0 (en) * 1993-06-07 1993-07-21 Iaf Biochem Int Stereoselective synthesis of nucleoside analogues using bicycle intermediate
ATE199906T1 (de) 1993-06-29 2001-04-15 Mitsubishi Chem Corp Phosphonat-nukleotid ester-derivate
AU690587B2 (en) 1993-09-17 1998-04-30 Gilead Sciences, Inc. Method for dosing therapeutic compounds
DE69435319D1 (de) 1993-09-17 2010-12-16 Gilead Sciences Inc Nukleotidanaloge
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
WO1995032957A1 (en) 1994-05-27 1995-12-07 Astra Aktiebolag Novel ethoxycarbonyloxymethyl derivatives of substituted benzimidazoles
US5514557A (en) 1994-06-06 1996-05-07 Genetic Testing Institute Inc. Method and kit for detecting antibodies specific for HLA and/or platelet glycoproteins
PE32296A1 (es) 1994-07-28 1996-08-07 Hoffmann La Roche Ester de l-monovalina derivado de 2-(2-amino-1,6-dihidro-6-oxo-purin-9-il) metoxi-1,3-propandiol y sus sales farmaceuticamente aceptables
US5512596A (en) * 1994-09-02 1996-04-30 Gilead Sciences, Inc. Aromatic compounds
US5486806A (en) * 1994-11-09 1996-01-23 Firari; Harold A. Anti-hijacking and theft prevention device for motor vehicles
US5684018A (en) 1994-12-13 1997-11-04 Merck & Co., Inc. Acyloxyisopropyl carbamates as prodrugs for amine drugs
MY115461A (en) 1995-03-30 2003-06-30 Wellcome Found Synergistic combinations of zidovudine, 1592u89 and 3tc
KR100571215B1 (ko) 1995-06-07 2006-10-24 트라이머리스 인코퍼레이티드 복합적인치료요법을이용한hiv와다른바이러스감염의치료
US5618964A (en) * 1995-06-07 1997-04-08 Bristol-Myers Squibb Company Prodrug esters of phosphonosulfonate squalene synthetase inhibitors and method
US5733788A (en) * 1996-07-26 1998-03-31 Gilead Sciences, Inc. PMPA preparation
CA2261619C (en) 1996-07-26 2006-05-23 Gilead Sciences, Inc. Nucleotide analogs
US5922695A (en) * 1996-07-26 1999-07-13 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
AU4428397A (en) * 1996-09-20 1998-04-14 Warner-Lambert Company Oral compositions containing a zinc compound
US6113920A (en) 1996-10-31 2000-09-05 Glaxo Wellcome Inc. Pharmaceutical compositions
GB9622681D0 (en) 1996-10-31 1997-01-08 Glaxo Group Ltd Pharmaceutical compositions
US5965729A (en) 1997-02-05 1999-10-12 Merck & Co., Inc. Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent
US6143877A (en) 1997-04-30 2000-11-07 Epoch Pharmaceuticals, Inc. Oligonucleotides including pyrazolo[3,4-D]pyrimidine bases, bound in double stranded nucleic acids
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
ZA986614B (en) 1997-07-25 1999-01-27 Gilead Sciences Nucleotide analog composition
EP1256584B1 (en) * 1997-07-25 2004-09-29 Gilead Sciences, Inc. Process for preparing Adefovir Dipivoxil
US6270957B1 (en) * 1997-08-26 2001-08-07 Wisconsin Alumni Research Foundation Non-Imuunosuppressive cyclosporins and their use in the prevention and treatment of HIV infection
CO4970782A1 (es) 1997-11-13 2000-11-07 Merck & Co Inc Terapia combinada para el tratamiento del sida
US6087383A (en) * 1998-01-20 2000-07-11 Bristol-Myers Squibb Company Bisulfate salt of HIV protease inhibitor
US6312662B1 (en) 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
US6127121A (en) 1998-04-03 2000-10-03 Epoch Pharmaceuticals, Inc. Oligonucleotides containing pyrazolo[3,4-D]pyrimidines for hybridization and mismatch discrimination
UA72207C2 (uk) * 1998-04-07 2005-02-15 Брістол- Майєрс Сквібб Фарма Компані Фармацевтична композиція ефавіренцу з добавкою дезінтегруючих агентів у вигляді швидкорозчинних капсул або таблеток та спосіб її виготовлення
US20020072493A1 (en) * 1998-05-19 2002-06-13 Yeda Research And Development Co. Ltd. Activated T cells, nervous system-specific antigens and their uses
EP1332757B1 (en) 1998-05-27 2012-06-13 Merck Sharp & Dohme Corp. Efavirenz compressed tablet formulation
US20010014352A1 (en) * 1998-05-27 2001-08-16 Udit Batra Compressed tablet formulation
CO5070643A1 (es) 1998-05-27 2001-08-28 Merck & Co Inc Formulacion en tabletas comprimidas
US6194391B1 (en) 1998-06-24 2001-02-27 Emory University 3′-azido-2′,3′-dideoxyuridine administration to treat HIV and related test protocol
RU2244712C2 (ru) * 1998-08-12 2005-01-20 Гайлид Сайенсиз, Инк. Способ получения 1,3-оксатиоланового нуклеозида, способ получения производного 1,3-оксатиоланил-5-она
GB9820420D0 (en) 1998-09-18 1998-11-11 Glaxo Group Ltd Antiviral combinations
GB9909154D0 (en) 1999-04-22 1999-06-16 Nippon Glaxo Limited Pharmaceutical formulation
US6660845B1 (en) 1999-11-23 2003-12-09 Epoch Biosciences, Inc. Non-aggregating, non-quenching oligomers comprising nucleotide analogues; methods of synthesis and use thereof
AU2001240578A1 (en) 2000-02-02 2001-08-14 Axxima Pharmaceuticals Ag Pharmaceutically active aromatic guanylhydrazones
EP1642582A1 (en) * 2000-02-29 2006-04-05 Bristol-Myers Squibb Company Low dose entecavir formulation and use
EP1363704A2 (en) 2000-12-15 2003-11-26 Triangle Pharmaceuticals Inc. Dapd combination therapy with inosine monophosphate dehydrogenase inhibitor
AU2002242096A1 (en) 2001-02-06 2002-08-19 The University Of Georgia Research Foundation, Inc. Novel compounds and methods for inhibiting/treating hiv infections and aids related symptoms
CN1503796B (zh) 2001-03-01 2012-07-04 三角药品公司 顺-ftc的多晶型物及其它晶型
MY169670A (en) 2003-09-03 2019-05-08 Tibotec Pharm Ltd Combinations of a pyrimidine containing nnrti with rt inhibitors
EP1448170A4 (en) 2001-11-27 2010-05-12 Bristol Myers Squibb Co EFAVIRENZ STAMP PREPARATIONS HAVING UNIQUE BIOPHARMACEUTICAL CHARACTERISTICS
ES2400138T3 (es) 2002-01-16 2013-04-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Comprimido farmacéutico de dos capas que comprende telmisartán y un diurético
AU2003210659A1 (en) * 2002-01-24 2003-09-02 Sangstat Medical Corporation Combination therapy for treatment of hiv infection
EA008775B1 (ru) 2002-04-26 2007-08-31 Джилид Сайэнс, Инк. Ингибиторы протеазы вич для лечения инфекции вич и фармацевтическая композиция
EP1569659A4 (en) 2002-12-09 2009-03-25 Univ Georgia Res Found DIOXOLAN THYMIN AND COMBINATIONS AGAINST 3TC / AZT RESISTANT HIV STRAINS
CA2509023C (en) * 2002-12-26 2011-05-24 Pozen Inc. Multilayer dosage forms containing nsaids and triptans
SI1583542T1 (sl) 2003-01-14 2008-12-31 Gilead Sciences Inc Sestavki in postopki za kombinacijsko antivirusnoterapijo
KR101125268B1 (ko) * 2003-06-06 2012-04-23 에띠팜 구강 분산성 다중층 정제
CA2598607A1 (en) 2005-01-18 2006-07-27 Adra N. Chaker Methods and compositions for cell-cycle regulation
TWI471145B (zh) * 2005-06-13 2015-02-01 Bristol Myers Squibb & Gilead Sciences Llc 單一式藥學劑量型
TWI375560B (en) 2005-06-13 2012-11-01 Gilead Sciences Inc Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same
US8232278B2 (en) 2005-06-24 2012-07-31 Gilead Sciences, Inc. Pyrido(3,2-D)pyrimidines and pharmaceutical compositions useful for treating hepatitis C
CA2616189C (en) * 2005-07-22 2019-03-26 Progenics Pharmaceuticals, Inc. Methods for reducing viral load in hiv-1-infected patients
US7448494B2 (en) * 2005-08-10 2008-11-11 Certain Teed Corporation Loose fill insulation packaged with additive
ATE474560T1 (de) 2005-12-14 2010-08-15 Cipla Ltd Pharmazeutische kombination aus nucleotid und nucleosid-reverse-transkriptase-hemmern (wie tenofovir und lamivudin) in verschiedenen teilen der dosiereinheit
GB0525898D0 (en) 2005-12-20 2006-02-01 Pharmo Bioscience As Screening compounds for activity in modulating chloride ion transport
JP2010515771A (ja) 2007-01-16 2010-05-13 プロテオロジクス リミテッド トポイソメラーゼインヒビターの治療効果を増強する方法
AU2009279604A1 (en) 2008-08-06 2010-02-11 Bionevia Pharmaceuticals, Inc. Flupirtine hydrochloride maleic acid cocrystal
WO2012003413A1 (en) 2010-06-30 2012-01-05 The Broad Institute, Inc. Novel solid forms of tacedinaline
UA114075C2 (xx) 2010-11-19 2017-04-25 БАГАТОШАРОВА ТАБЛЕТКА, ЩО МІСТИТЬ РИЛПІВІРИН HCl, ЕМТРИЦИТАБІН І ТЕНОФОВІРУ ДИЗОПРОКСИЛФУМАРАТ

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025797A1 (en) * 1998-11-02 2000-05-11 Triangle Pharmaceuticals, Inc. Combination therapy to treat hepatitis b virus
WO2002008241A2 (en) * 2000-07-21 2002-01-31 Gilead Sciences, Inc. Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Anti-HIV drug updates--three drugs on the near horizon.", PROJECT INFORM PERSPECTIVE. JAN 2003, no. 35, January 2003 (2003-01-01), pages 4 - 7, XP001181983 *
DE CLERCQ ERIK: "New anti-HIV agents and targets", MEDICINAL RESEARCH REVIEWS, vol. 22, no. 6, November 2002 (2002-11-01), pages 531 - 565, XP002284899, ISSN: 0198-6325 *
MULATO A S ET AL: "ANTI-HIV ACTIVITY OF ADEFOVIR (PMEA) AND PMPA IN COMBINATION WITH ANTIRETROVIRAL COMPOUNDS: IN VITRO ANALYSES", ANTIVIRAL RESEARCH, ELSEVIER SCIENCE BV., AMSTERDAM, NL, vol. 36, no. 2, November 1997 (1997-11-01), pages 91 - 97, XP000890091, ISSN: 0166-3542 *
MURRY, JEFFREY P. ET AL: "Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir , even in the presence of lamivudine", JOURNAL OF VIROLOGY , 77(2), 1120-1130 CODEN: JOVIAM; ISSN: 0022-538X, 12 January 2003 (2003-01-12), XP002284898 *
RICHMAN D D: "Antiretroviral activity of emtricitabine, a potent nucleoside reverse transcriptase inhibitor.", ANTIVIRAL THERAPY. JUN 2001, vol. 6, no. 2, June 2001 (2001-06-01), pages 83 - 88, XP009032162, ISSN: 1359-6535 *
RISTIG MARIA B ET AL: "Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed.", JOURNAL OF INFECTIOUS DISEASES, vol. 186, no. 12, 15 December 2002 (2002-12-15), pages 1844 - 1847, XP002284897, ISSN: 0022-1899 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1819323B2 (en) † 2004-12-03 2023-03-22 Merck Sharp & Dohme Corp. Pharmaceutical composition containing an anti-nucleating agent
EP1819323B1 (en) 2004-12-03 2016-11-16 Merck Sharp & Dohme Corp. Pharmaceutical composition containing an anti-nucleating agent
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
WO2013115916A1 (en) * 2012-02-03 2013-08-08 Gilead Sciences, Inc. Combination therapy comprising gs-7340 and cobicistat for use in the treatment of viral infections
WO2015028875A3 (en) * 2013-08-29 2015-11-19 Teva Pharmaceuticals Industries Ltd. Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2018153977A1 (en) * 2017-02-24 2018-08-30 Hexal Ag Stable composition of tenofovir alafenamide
WO2019113462A1 (en) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11331331B2 (en) 2017-12-07 2022-05-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11903959B2 (en) 2017-12-07 2024-02-20 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

Also Published As

Publication number Publication date
NZ540728A (en) 2008-08-29
EP1583542A1 (en) 2005-10-12
EP1923063A3 (en) 2009-04-08
JP2019052174A (ja) 2019-04-04
EP3025718A1 (en) 2016-06-01
PL408254A1 (pl) 2014-07-21
JP2006516570A (ja) 2006-07-06
AU2004206821A1 (en) 2004-08-05
IS7977A (is) 2005-08-12
BRPI0406760A (pt) 2005-12-20
US20090036408A1 (en) 2009-02-05
CY1108355T1 (el) 2014-02-12
US9457036B2 (en) 2016-10-04
CA2512319A1 (en) 2004-08-05
JP2010120957A (ja) 2010-06-03
WO2004064845A8 (en) 2004-09-23
US20170232019A1 (en) 2017-08-17
SI1583542T1 (sl) 2008-12-31
US20150111856A1 (en) 2015-04-23
US20140213556A1 (en) 2014-07-31
WO2004064845A1 (en) 2004-08-05
US20150111855A1 (en) 2015-04-23
KR20080032014A (ko) 2008-04-11
CA2512475A1 (en) 2004-08-05
EP1583542B9 (en) 2008-10-22
AP2089A (en) 2010-01-11
HRP20140379A2 (hr) 2014-07-18
AU2009200414A1 (en) 2009-02-26
AU2004206827A1 (en) 2004-08-05
US8716264B2 (en) 2014-05-06
IL169243A (en) 2008-12-29
NO20150656A1 (no) 2005-10-13
US20040224916A1 (en) 2004-11-11
CN102670629A (zh) 2012-09-19
US20170273994A1 (en) 2017-09-28
US8592397B2 (en) 2013-11-26
ES2308136T3 (es) 2008-12-01
US20090143314A1 (en) 2009-06-04
CN102670629B (zh) 2016-02-24
EA200501134A1 (ru) 2005-12-29
JP2014037430A (ja) 2014-02-27
CN105596356A (zh) 2016-05-25
DE602004014470D1 (de) 2008-07-31
DK1583542T3 (da) 2008-09-22
NO20053817L (no) 2005-10-13
JP2017057232A (ja) 2017-03-23
HK1079122A1 (en) 2006-03-31
AU2009200414B2 (en) 2011-12-08
KR100860136B1 (ko) 2008-09-25
KR20090053867A (ko) 2009-05-27
EA201100293A1 (ru) 2011-08-30
EP1923063A2 (en) 2008-05-21
US20060234982A1 (en) 2006-10-19
JP2021004264A (ja) 2021-01-14
EA015145B1 (ru) 2011-06-30
AU2004206821C1 (en) 2009-10-01
EP1585527A1 (en) 2005-10-19
PT1583542E (pt) 2008-09-17
HRP20050619A2 (en) 2005-10-31
JP2015098488A (ja) 2015-05-28
JP4996241B2 (ja) 2012-08-08
CA2512475C (en) 2009-06-02
PL378368A1 (pl) 2006-04-03
JP2006515624A (ja) 2006-06-01
NO340951B1 (no) 2017-07-24
US20040224917A1 (en) 2004-11-11
NO20053817D0 (no) 2005-08-12
NO20171193A1 (no) 2005-10-13
EP1583542B1 (en) 2008-06-18
KR20050092755A (ko) 2005-09-22
US9744181B2 (en) 2017-08-29
AU2004206821B2 (en) 2009-02-26
ATE398455T1 (de) 2008-07-15
AP2005003348A0 (en) 2005-06-30
NO337917B1 (no) 2016-07-11
MXPA05007016A (es) 2005-09-12
US20060246130A1 (en) 2006-11-02

Similar Documents

Publication Publication Date Title
AU2004206821C1 (en) Compositions and methods for combination antiviral therapy
AU2011253996B2 (en) Compositions and methods for combination antiviral therapy
DAHL et al. Patent 2512475 Summary
AU2014216017A1 (en) Compositions and methods for combination antiviral therapy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 540877

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2004206827

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2512319

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2004701840

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006500943

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2004206827

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2004701840

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006234982

Country of ref document: US

Ref document number: 10540782

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 10540782

Country of ref document: US